Laura Bergantini

Background: Interstitial lung disease (ILD) is an increasingly recognized manifestation of ANCA-associated vasculitis (AAV) and is associated with substantial morbidity and mortality. The marked biological and clinical heterogeneity of AAV-associated ILD (AAV-ILD) poses major challenges for diagnosis, prognostic stratification, and therapeutic decision-making. Circulating biomarkers have emerged as promising tools for improving disease characterization; however, the available evidence remains limited and fragmented. Methods: We performed a scoping review to summarize the current evidence on circulating biomarkers investigated in AAV-ILD. Peer-reviewed studies evaluating biomarkers associated with ILD occurrence, disease activity, radiological progression, pulmonary function decline, mortality, or treatment response were systematically identified and qualitatively analyzed. Results: Seven observational studies met the inclusion criteria. The identified biomarkers could be broadly classified into three biological categories: epithelial injury biomarkers (KL-6 and SP-D), immune–fibrotic biomarkers (CCL2, CXCL6, CXCL13, and IL-13), and epithelial remodelling biomarkers (CA19-9, CA125, and CYFRA21-1). KL-6 and SP-D were associated across individual studies with pulmonary involvement, disease activity, or relapse, whereas CCL2, CXCL6, CXCL13, and IL-13 were associated with inflammatory and profibrotic processes, radiological abnormalities, or disease progression. Tumour-associated biomarkers were associated with radiological abnormalities and mortality, suggesting that they may reflect aberrant epithelial remodelling rather than malignancy. Across studies, circulating biomarkers showed preliminary associations with disease detection, prognosis, longitudinal disease behaviour, and treatment response; however, their clinical utility has not been prospectively established. Overall, the current evidence is limited by small sample sizes, retrospective study designs, and substantial clinical heterogeneity. Conclusions: Circulating biomarkers represent a promising approach for improving the biological characterization of AAV-ILD and may contribute to the future characterization of inflammatory and fibrotic disease phenotypes. Prospective multicentre studies with independent validation cohorts are required before biomarker-guided management can be implemented in routine clinical practice.

Background: Interstitial lung disease (ILD) is an increasingly recognized manifestation of ANCA-associated vasculitis (AAV) and is associated with substantial morbidity and mortality. The marked biological and clinical heterogeneity of AAV-associated ILD (AAV-ILD) poses major challenges for diagnosis, prognostic stratification, and therapeutic decision-making. Circulating biomarkers have emerged as promising tools for improving disease characterization; however, the available evidence remains limited and fragmented. Methods: We performed a scoping review to summarize the current evidence on circulating biomarkers investigated in AAV-ILD. Peer-reviewed studies evaluating biomarkers associated with ILD occurrence, disease activity, radiological progression, pulmonary function decline, mortality, or treatment response were systematically identified and qualitatively analyzed. Results: Six observational studies met the inclusion criteria, comprising four retrospective and two prospective cohorts. The identified biomarkers could be broadly classified into three biological categories: epithelial injury biomarkers (KL-6 and surfactant protein D [SP-D]), immune–fibrotic biomarkers (C-C motif chemokine ligand 2 [CCL2] and C-X-C motif chemokine ligand 6 [CXCL6]), and epithelial remodelling biomarkers (carbohydrate antigen 19-9 [CA19-9], cancer antigen 125 [CA125], and cytokeratin-19 fragment [CYFRA21-1]). KL-6 and SP-D were consistently associated with pulmonary involvement, disease activity, and relapse, whereas CCL2 and CXCL6 reflected inflammatory and profibrotic pathways linked to disease progression. Tumour-associated biomarkers were associated with radiological abnormalities and mortality,suggesting that they may reflect aberrant epithelial remodelling rather than malignancy. Across studies, circulating biomarkers showed potential utility for disease detection, prognostic stratification, longitudinal monitoring, and therapeutic guidance. However, the current evidence is limited by small sample sizes, retrospective study designs, and substantial clinical heterogeneity. Conclusions: Circulating biomarkers represent a promising approach for improving the biological characterization of AAV-ILD and may facilitate more personalized management strategies by distinguishing inflammatory from fibrotic disease phenotypes. Prospective multicentre studies with independent validation cohorts are required before biomarker-guided management can be implemented in routine clinical practice.

Background and objectiveSarcoidosis is a multisystem granulomatous disease with a variable clinical course. While many patients experience spontaneous remission, a substantial proportion develop chronic or relapsing disease requiring prolonged systemic therapy, most commonly corticosteroids. In real-world practice, treatment initiation, tapering strategies, and duration of therapy are heterogeneous, and data on the long-term impact of treatment on comorbidity burden are limited. MethodsWe conducted a retrospective, monocentric observational study including adults with sarcoidosis followed at a tertiary center from January 2010 to November 2025. Demographic, clinical, radiological and therapeutic data were extracted from records. Baseline strategies, corticosteroid exposure, and initiation of immunosuppression were recorded. Associations between treatment exposure and comorbidities were evaluated using regression. ResultsA total of 835 patients were included. At baseline, 81.8% received pharmacologic treatment, most commonly corticosteroids alone. Extrapulmonary involvement was present in 45.4% of patients and was the main determinant of treatment initiation and escalation to immunosuppressive therapy. During follow-up, 664 patients received systemic corticosteroids for a mean cumulative duration of 38.4 ± 64.3 months, and 25.9% required immunosuppressive agents, predominantly methotrexate. Hypertension and bone mineral density impairment were the most frequent comorbidities. Cumulative corticosteroid exposure, but not baseline dose, was independently associated with both hypertension and bone disease. Immunosuppressive therapy was not associated with overall comorbidity burden. ConclusionTreatment decisions were driven primarily by disease phenotype, particularly extrapulmonary involvement. Cumulative corticosteroid exposure was independently associated with hypertension and bone disease. These findings support earlier steroid-sparing strategies and the need for more standardized long-term management.

Introduction: Severe asthma (SA) is characterized by airway inflammation that is refractory to oral corticosteroids (OCS). The anti–IL-5R moAb benralizumab has been introduced as a novel therapeutic option. Benralizumab exerts its action through its constant (Fc) fragment, which binds to CD16a receptors on the surface of natural killer (NK) cells. Recent studies have reported that NK cell–mediated resolution of inflammation is impaired in SA. However, the combined effects of benralizumab and OCS therapy have not been previously investigated. Aim:We aimed to analyse changes in NK cells in SA before and after benralizumab therapy, with a particular focus on the impact of concomitant OCS use. Methods: 28 SA were recruited at Siena University Hospital. PBMCs were collected at baseline and after six months of benralizumab therapy. NK cell subsets were analysed by flow cytometry.Results: SA who continued OCS use prior to benralizumab administration showed increased frequencies of CD56dimNK cells expressing the inhibitory markers NKG2A and KIR. After six months of benralizumab treatment, no significant differences in NK cell subset distribution were observed between SA with or without baseline OCS use. Moreover, SA who discontinued OCS during benralizumab therapy exhibited a rebalancing of CD56dim NK cells. In SA, KIR expression shifted toward more immature NK cells expressing only NKG2A. Similar findings were observed in SA treated with benralizumab alone. Conclusions: SA display reduced NK cell cytotoxicity, further impaired by corticosteroids. The restoration of NK suggests that OCS induced dysfunction contributes to persistent inflammation in SA.

Clinical remission on biologic treatment has emerged as a relevant target in severe asthma management. Simple and widely available type 2 (T2) biomarkers, such as fractional exhaled nitric oxide (FeNO) and blood eosinophil count (BEC), may help stratify patients in real-world practice. To explore whether the combined baseline assessment of FeNO and BEC is associated with clinical remission at 12 months in patients with severe eosinophilic asthma (SEA) treated with biologic therapy. In this prospective real-world single-center study, 69 patients with severe asthma initiating benralizumab (n = 26), mepolizumab (n = 16), or dupilumab (n = 27) were enrolled. At baseline, patients were classified as dual high biomarker T2 (DHB-T2: FeNO50 ≥ 25 ppb and BEC ≥300 cells/µL) or heterogeneous/no biomarker T2 (HNB-T2: all other biomarker combinations). Clinical remission at 12 months was defined by the simultaneous fulfilment of the following criteria: absence of maintenance oral corticosteroids, zero exacerbations, FEV1 ≥ 80% predicted, and Asthma Control Test (ACT) score ≥20. At 12 months, 42 of 69 patients (60.8%) achieved clinical remission. DHB-T2 status was associated with a higher likelihood of remission (univariate OR 4.58, p = 0.005; multivariate OR 12.67, p = 0.002). The DHB-T2 classification showed a sensitivity of 73.33% and a specificity of 62.45% for identifying patients achieving remission. Isolated baseline elevation of either FeNO or BEC alone was not associated with clinical remission. In this real-world cohort of patients with severe eosinophilic asthma treated with biologics, concomitant baseline elevation of FeNO and blood eosinophils was associated with a higher likelihood of achieving clinical remission at 12 months.

The heterogeneity of the inflammatory patterns underlying the pathogenesis of severe asthma has led to the identification of different disease endotypes: in particular, severe eosinophilic asthma (...

Natural Killer (NK) cells contribute to airway inflammation in severe eosinophilic asthma (SEA). IL-33, elevated in SEA, may modulate NK cell function, but its effects are unclear. We analyzed peripheral blood NK cell subsets from five SEA patients and five healthy controls using flow cytometry, assessing CD56/CD16-defined subsets and markers, CD57, NKG2A, CD62L, and ICAM-1, at baseline and after 72 h IL-33 stimulation. SEA patients showed reduced mature cytotoxic NK cells and altered expression of adhesion and regulatory molecules. IL-33 selectively increased ICAM-1 and NKG2A in mature NK cells, while decreasing these markers in immature subsets. These findings indicate that IL-33 differentially regulates NK-cell phenotype and function, highlighting NK cells as dynamic mediators of inflammation in SEA.

Introduction: Sarcoidosis is a systemic granulomatous disorder classified among interstitial lung diseases (ILDs). While the lungs and intrathoracic lymph nodes are most affected, the disease can involve multiple organs. The heterogeneity of clinical presentation arises from complex interactions between environmental exposures and immune responses in genetically susceptible individuals. Sex-dependent genetic variations are associated with differences in phenotype and organ localization. Gender-related factors also influence the impact of sarcoidosis on quality of life and health perception, contributing to variability in disease burden and outcomes. Aim of the study: to provide an overview of sex- and gender-related differences in sarcoidosis, focusing on pathophysiological and clinical implications. Material and Methods: The systematic search was conducted on Medline database through Pubmed search engine. We included all clinical studies from 1992 to the present, and imposed language restrictions, accepting only English publications. Case reports, reviews, and pre-print studies were excluded. Results: A total of 35 studies were included. Sex differences significantly influenced both age of onset and clinical presentation of the disease. Women received a diagnosis of sarcoidosis at an older age and exhibited more frequently extrapulmonary localizations, with predominant involvement of the eyes, skin, and extra-thoracic lymph nodes. In contrast, men more commonly presented with limited pulmonary forms. Löfgren syndrome was more prevalent among women and appeared to be associated with sex-specific genetic variations, particularly within the MHC region. Gender differences also impacted quality of life and disease perception: women reported a lower quality of life and were more susceptible to anxiety and depression throughout the disease course. Conclusions: This report confirms that clinical presentation of sarcoidosis is significantly influenced by sex and gender. The identification of sex- and gender-specific clinical patterns supports a personalized medicine framework, in which diagnostic assessment, monitoring strategies, and therapeutic approaches may be tailored according to individual biological and gender-related characteristics.

Background: Nitric oxide (NO) is a gaseous free radical produced from L-arginine by the nitric oxide synthase (NOS) enzymes. NO exerts a dose-dependent biphasic effect on lung cancer development, angiogenesis, and dissemination. The widespread contribution of nitric oxide signaling to lung cancer biology has cast a spotlight on the identification of NO-based therapeutic approaches as well as the use of fractional exhaled NO (FeNO) as a prognostic biomarker of clinical control. However, the significance of lung cancer treatment and prognosis has not been fully elucidated. Objective: This narrative review gives an overview of NO in lung cancer, focusing on its therapeutic and prognostic implications. Results: FeNO may help to assess the complications associated with non-pharmacological treatments, including postoperative pneumonia and radiation pneumonitis. By contrast, the role of FeNO dynamics during pharmacological treatment is still largely unexplored due to the suppressive effect of chemotherapy on FeNO levels. The rise of immunotherapy may pave the way to a better evaluation of FeNO as a prognostic biomarker of treatment response. The dichotomous involvement of NO in lung cancer events has led to the adoption of several NO-centered treatments that are focused on both inhibiting and enhancing NO signaling. However, NO chemical and biological characteristics have hindered its implementation in clinical practice. Conclusions: In the coming years, the advancements in drug delivery systems may lead to more effective anti-cancer applications of NO by improving tumor targeting and minimizing the systemic side effects. Together, our findings emphasize the promising role of NO in lung cancer treatment, underscoring the challenges and avenues for future research.

Lung cancer remains the leading cause of cancer-related mortality worldwide, characterized by its complexity and heterogeneity